Early sex-dependent differences in response to environmental stress

in Reproduction

Developmental plasticity enables the appearance of long-term effects in offspring caused by exposure to environmental stressors during embryonic and foetal life. These long-term effects can be traced to pre- and post-implantation development, and in both cases, the effects are usually sex specific. During preimplantation development, male and female embryos exhibit an extensive transcriptional dimorphism mainly driven by incomplete X chromosome inactivation. These early developmental stages are crucial for the establishment of epigenetic marks that will be conserved throughout development, making it a particularly susceptible period for the appearance of long-term epigenetic-based phenotypes. Later in development, gonadal formation generates hormonal differences between the sexes, and male and female placentae exhibit different responses to environmental stressors. The maternal environment, including hormones and environmental insults during pregnancy, contributes to sex-specific placental development that controls genetic and epigenetic programming during foetal development, regulating sex-specific differences, including sex-specific epigenetic responses to environmental hazards, leading to long-term effects. This review summarizes several human and animal studies examining sex-specific responses to environmental stressors during both the periconception period (caused by differences in sex chromosome dosage) and placental development (caused by both sex chromosomes and hormones). The identification of relevant sex-dependent trajectories caused by sex chromosomes and/or sex hormones is essential to define diagnostic markers and prevention/intervention protocols.

Abstract

Developmental plasticity enables the appearance of long-term effects in offspring caused by exposure to environmental stressors during embryonic and foetal life. These long-term effects can be traced to pre- and post-implantation development, and in both cases, the effects are usually sex specific. During preimplantation development, male and female embryos exhibit an extensive transcriptional dimorphism mainly driven by incomplete X chromosome inactivation. These early developmental stages are crucial for the establishment of epigenetic marks that will be conserved throughout development, making it a particularly susceptible period for the appearance of long-term epigenetic-based phenotypes. Later in development, gonadal formation generates hormonal differences between the sexes, and male and female placentae exhibit different responses to environmental stressors. The maternal environment, including hormones and environmental insults during pregnancy, contributes to sex-specific placental development that controls genetic and epigenetic programming during foetal development, regulating sex-specific differences, including sex-specific epigenetic responses to environmental hazards, leading to long-term effects. This review summarizes several human and animal studies examining sex-specific responses to environmental stressors during both the periconception period (caused by differences in sex chromosome dosage) and placental development (caused by both sex chromosomes and hormones). The identification of relevant sex-dependent trajectories caused by sex chromosomes and/or sex hormones is essential to define diagnostic markers and prevention/intervention protocols.

Introduction

Thefoetal origins of adult disease hypothesis (so-called ‘Barker hypothesis’) (Barker & Osmond 1986) proposes that undernutrition during gestation is, in part, responsible for adult cardiac and metabolic disorders due to foetal programming in utero that permanently shapes the body’s structure, function and metabolism and contributes to susceptibility to adult diseases. This hypothesis has led to a wider theory, known as the ‘Developmental Origins of Health and Disease (DOHaD)’, which is based on developmental plasticity (the ability of the genotype to produce different phenotypes in response to different environments) and the concept of evolutionary mismatch (evolved traits that were once advantageous but became maladaptive due to changes in the environment). There are several critical stages when development is malleable (periconception, pregnancy and early postnatal life) and exhibits an enhanced plasticity that enables the organism to fine-tune epigenetic control of gene expression in accordance with environmental cues. During these periods, the embryo can adapt to novel conditions and diverse environments, reprograming developmental trajectories in order to confer the best chance of survival and reproductive success. However, these adaptive changes can conflict with the postnatal environment and impair adult heath. The time of maximal plasticity appears during periconception, as plasticity is reduced progressively as foetal development proceeds (Fig. 1). There are three key periods (embryonic, foetal, lactation) during which environmental stress exerts a greater effect. Sexual dimorphism in the DOHaD context of health and disease is a phenomenon among a variety of species, but it generally occurs in most common noncommunicable diseases (NCDs), including cardiovascular disease, metabolic diseases, hypertension, neurological disorders and cancer (Junien et al. 2012, Kalisch-Smith et al. 2017). NCDs continue to be the leading cause of deaths worldwide and were responsible for 38 million of the world’s 56 million deaths in 2012, and WHO predicts a 17% increase in NCDs during the next decade (Mendis et al. 2015). The concept of DOHaD represents an important approach to the understanding and prevention of the alarming and increasing incidence of NCD, as recent studies of variable regions of neonatal methylome demonstrate that the interaction of genotype with the uterine environment accounts for 75% of unexplained variability (Teh et al. 2014).

Figure 1
Figure 1

Pre- and peri-implantation embryo adaptations to environmental stress. Comparative pre- and peri-implantation embryo development in mammals. Critical events taking place during this developmental window (pluripotency emergence, epigenetic reprogramming, lineage allocation and X chromosome inactivation) render the embryo especially sensitive to environmental stress. Such embryos and the resulting foetus respond to stressors by sex-specific mortality or by adaptive responses in order to optimize their developmental program and offspring survival. The adaptability due to developmental plasticity (the ability of the genotype to produce different phenotypes in response to different environments) decrease throughout embryo and foetal development until early postnatal life. Later in adult life, this adaptability disappears and only the brain maintains a certain degree of plasticity. The female placenta (in pink), due to its higher adaptability, buffers more efficiently the impact of endogenous and exogenous stressors on the foetus and it is less compromised than male foetus (in blue) under similar stress conditions. However, compensatory mechanisms can compromise adult health according to the developmental origins of adult health and disease (DOHaD).

Citation: Reproduction 155, 1; 10.1530/REP-17-0466

In the context of DOHaD, the epigenetic marks that respond to the environment register the effects during the development of a specific sex (Heijmans et al. 2009). Environmental epigenetics investigates environmental factors that impact on the organism to modulate the expression of genes across the life course. The two most prominent stages are the perimplantation period and the period of foetal development, where epigenetic alterations may affect not only birth outcomes but also lifelong health. Some early environmental events such as stress, nutrition, behavior and environmental pollutants may disturb the precisely timed processes that sculpt the embryo and foetus in a sex-dependent manner and thus influence its health in later life (Attig et al. 2010). We have reported that sex differences in embryonic metabolism, gene expression and epigenetics start from the blastocyst stage (Gutierrez-Adan et al. 2000, 2006, Bermejo-Alvarez et al. 2008), and these differences are caused by extra gonadal and dosage effects of genes encoded on sex chromosomes. Sex has been proposed as a major factor determining the type and severity of the long-term effects originating during the preimplantation period (Bermejo-Alvarez et al. 2011a). Preimplantation developmental plasticity has evolved in order to offer the best chances of survival under changing environments. Conversely, environmental conditions experienced in early life can dramatically influence neonatal and adult biology, which may result in detrimental long-term effects (Laguna-Barraza et al. 2012). There are many human and animal studies demonstrating sexual differences in response to various developmental insults during periconception (Fleming et al. 2015a) and pregnancy (Sundrani et al. 2017) and demonstrating sexual differences in response to various developmental insults during pregnancy (Sundrani et al. 2017). However, there is a gap in knowledge of the mechanism(s) mediating environmental and maternal programing of preimplantation development. For example, how can environmental conditions during the preimplantation period have a long-term effect? How does the early embryo sense its environment and how are morphogenesis, metabolism, genetic and epigenetic alterations induced? What are the sex-specific differences and how are they maintained, erased or gave rise to new ones?

Preimplantation embryo development, a crucial period for the appearance of sex-specific long-term effects

Sex differences in gene expression emerge with embryonic genome activation, and they are dynamic throughout the lifespan. Although some authors have suggested that transcriptional sex differences are higher in adult tissues compared with preimplantation embryos at the 8-cell stage (Lowe et al. 2015), no transcriptional analysis in adult tissues has reported the massive transcriptional sex differences observed in both mouse (Kobayashi et al. 2006) and bovine (Bermejo-Alvarez et al. 2010) blastocysts. Preimplantation embryo development constitutes a critical period for the establishment of epigenetic marks, being one of the two unique moments during the lifespan where genome-wide demethylation occurs (Seisenberger et al. 2012). During these early developmental stages, key epigenetic processes, such as X chromosome inactivation (XCI) or initial telomere lengthening, take place (de Frutos et al. 2016). These dynamic changes of the epigenetic landscape exert a double impact on sex-specific long-term effects. On the one hand, incomplete XCI results in sex-unbalanced expression of X-linked genes, leading not only to an upregulation of these genes in females, but also to a genome-wide sex-specific transcriptional regulation in autosomal genes. On the other hand, the dynamic changes in the epigenome make this period particularly vulnerable to the appearance of aberrant epigenetic marks. In this perspective, the combination of the greatest transcriptional sexual dimorphism with the most susceptible period for the appearance of stable epigenetic alterations results in the most relevant period for the generation of sex-specific responses to stressors, leading to sex-specific phenotypic consequences for the offspring (Table 1).

Table 1

Different studies showing sex-specific effects of environmental alterations during preimplantation development, either in vivo through maternal stress or in vitro by assisted reproductive technologies (ARTs).

TreatmentEffectReference
Both sexesFemales onlyMales only
Maternal stress
MouseHeat stress-induced oxidative damage in pregnant mice and in vitro cultured embryosIncreased embryo lossPerez-Crespo et al. (2005)
SheepRestriction of B vitamins and methionine in maternal dietObesity, insulin resistance, elevated blood pressure, DNA methylation alterationsMore severe phenotypeSinclair et al. (2007)
Mouse, ratLow-protein maternal dietCardiovascular, metabolic and behavioural alterationsMore severe phenotypeFleming et al. (2015b)
Assisted reproductive technologies
BovineHigh glucose environment in vitroIncreased embryo lossGutierrez-Adan et al. (2001)
Mouse, bovineHigh glucose environment in vitroIncreased apoptosisIncreased survival and implantationJimenez et al. (2003)
MouseIn vitro culture with serumAltered behavior, imprinted genes expressionIncreased body weight, liver steatosisHyperactivity, anxietyFernandez-Gonzalez et al. (2004)
MouseIn vitro culture without CSH2Restricted foetal growth, increased body weight and adiposity, placenta alterationsIncreased body weight and adiposity, decreased brain sizeSjoblom et al. (2005)
MouseICSI with DNA-fragmented spermReduced embryo development and offspring, altered gene transcription and methylation, increased mortality, premature agingBehavioural alterations, higher body weight and organ size, increased tumor incidenceDelayed active demethylation of male pronucleusFernandez-Gonzalez et al. (2008)
MouseIVF, ISCI, SCNTIncreased body weightAltered glucose clearance, higher body weight and adiposityScott et al. (2010)
MouseIVFIncreased body weight and heart size, glucose intoleranceDonjacour et al. (2014)
MouseIVFSex-specific differences in sterol metabolism, redox state, mobilization and oxidation of fatty acidsIncreased fat accumulation, altered fat metabolite compositionAltered liver metabolite compositionFeuer et al. (2014)
MouseIVFIncreased apoptosis and pregnancy lossPlacental overgrowth, postnatal overgrowthTan et al. (2016)

Sex chromosomes drive sex differences in the absence of gonads

In the absence of gonads, and therefore without any sex-specific hormonal bias, sexual dimorphism during the preimplantation period relies solely on the differences in sex chromosome dosage. Thus, Y-linked genes will only be expressed in males, whereas X-linked genes will be upregulated in females if XCI is not accomplished, which is actually the case for most preimplantation embryos (Bermejo-Alvarez et al. 2012a). The dynamics and mechanism leading to XCI during preimplantation development have been the subject of debate over the last 10 years. Initial experiments conducted in the mouse observed that XCI was effectively accomplished in an imprinted manner by the blastocyst stage, experiencing a reactivation exclusively in the inner cell mass (Kay et al. 1994). This situation was thought to be comparable to other mammalian species, but transcriptional studies in bovine blastocysts refuted this notion, as most X-linked genes were upregulated in female blastocysts compared to their male counterparts (Bermejo-Alvarez et al. 2010). This situation was also observed in rabbit and human blastocysts by conducting in situ hybridization (ISH) studies (Okamoto et al. 2011), and in pigs, by transcriptional (Park et al. 2012) and methylation analyses (Hwang et al. 2015), so the mouse model was deemed to be more an exception than a rule for XCI dynamics (Bermejo-Alvarez et al. 2012a). Indeed, bovine (Bermejo-Alvarez et al. 2010) and rabbit (Okamoto et al. 2011) embryos achieve extensive XCI later, around the time of gastrulation, which opens a large window when the upregulation of X-linked genes in female embryos occurs and provides a molecular basis for the appearance of sex-specific phenotypes. In the case of human embryos, a recent study using single-cell RNA-Seq has observed that before XCI is accomplished, biallelic expression of XIST in female embryos causes progressive dampening of X chromosome expression (Petropoulos et al. 2016), an unexpected phenomenon that urges the revisiting of XCI dynamics in human stem cells (Lamas-Toranzo et al. 2017). This progressive downregulation, occurring in both X-chromosomes, gradually compensates for the differences in the expression of X-linked genes between the sexes, but it still leaves a large period of significant transcriptional sexual dimorphism – almost all preimplantation development, in fact – which may result in sex-specific long-term effects.

Sex chromosomes regulate autosomes, amplifying transcriptional sex differences

Sex-biased expression of Y- and X-linked genes is not the only transcriptional difference between male and female preimplantation embryos. Extensive transcriptional sex differences, affecting not only genes located on sex chromosomes but also many autosomal genes has been uncovered in preimplantation embryos by genome-wide transcriptional analyses in mice (Kobayashi et al. 2006) and, especially, cattle blastocysts, where almost one-third of the genes actively expressed showed transcriptional sex differences (Bermejo-Alvarez et al. 2010). The wider extent of transcriptional sex differences in bovine blastocysts compared with murine can be explained as a consequence of the incomplete XCI status in cattle compared to mice. In agreement with this notion, transcriptional sex differences are dramatically reduced in more advanced stages of bovine embryogenesis, such as in Day 14 (Bermejo-Alvarez et al. 2011b) or Day 19 (Forde et al. 2016) elongated conceptuses, once XCI has been mostly accomplished. Besides, gene co-expression networks analysis between X-linked genes upregulated in bovine female blastocysts and autosomal genes showing transcriptional sex-dependent differences has identified a major module of autosomal genes for which sex differences are likely driven by the X genes (Itoh & Arnold 2014). Effects of X chromosome on autosomal transcriptional regulation are also evident in sex-reversed mouse models: over 1000 autosomal genes were found differentially expressed between XY and XX males or XX and XY females (Wijchers et al. 2010).

The mechanisms by which upregulated X-linked genes affect the expression of autosomal genes remain to be determined; however, the presence of different genes encoding for chromatin modifiers on the X chromosome provides a plausible explanation. Both KDM5C (H3K4 demethylase, also known as JARID1C) and UTX (H3K27 demethylase, also known as KDM6A) are X-linked genes, and the chromatin marks they regulate are particularly relevant for preimplantation development. H3K4me3 is involved in transcriptional activation, whereas H3K27me3 is associated with transcriptional repression. Both opposing marks are present in early blastomeres on the promoters for genes involved in early cell differentiation. Bivalent domains keep these genes, including Sox2, Lifr, Nanog, Cdx2, Eomes and Tbpa, poised for activation, occurring once they lose the repressive H3K27me3 mark (Dahl et al. 2010). Given the sex differences in the transcription of key regulators of these bivalent domains, the effect of different stressors on the differentiation processes occurring during preimplantation development may also be sex specific. This effect may depend on the stressor, as although high glucose exposure does not have a sex-dependent effect on inner cell mass and trophectoderm cell counts in mouse blastocysts (Bermejo-Alvarez et al. 2012b), human male blastocysts have been reported to exhibit a better quality trophectoderm (TE) than female when cultured in vitro (Ebner et al. 2016), which may have short-term consequences on implantation or long-term consequences on placental development.

Developmental consequences of preimplantation transcriptional sex differences

Genes which transcription is sex dependent exert different functions which may determine a sex-specific response to a given stressor (Fig. 1). Metabolic differences between male and female embryos could determine a differential response to nutritional stress that may result in sex-specific early embryonic death or long-term effects. Glucose metabolism was initially reported to be different between sexes based on the upregulation of glucose-6-phosphate dehydrogenase (G6PD) in bovine (Gutierrez-Adan et al. 2000, Wrenzycki et al. 2002) and human (Taylor et al. 2001) female blastocysts, and on the overexpression of the autosomal SLC2A3 in bovine male blastocysts (Morton et al. 2007). However, gene ontology analysis of global transcriptional differences between male and female bovine blastocysts did not highlight glucose metabolism as a sexually dimorphic pathway (Bermejo-Alvarez et al. 2010). The specific transcriptional analysis of genes involved in either anaerobic glycolysis or the pentose phosphate pathway do not show a clear sex bias (Bermejo-Alvarez et al. 2011a), and the transcriptional response of bovine blastocysts to the presence of glucose was found to be unrelated to sex (Cagnone et al. 2011), all in agreement with the overall inconsistent reports regarding glucose-mediated sex biases (reviewed in Bermejo-Alvarez et al. 2012b). On the other hand, gene ontology analysis of bovine blastocysts highlighted mitochondria and protein translation, proteolysis and protein transport as sex-dependent pathways (Bermejo-Alvarez et al. 2010), which correlates with the differences between sexes in mtDNA content (Bermejo-Alvarez et al. 2008) and amino acid metabolism (Sturmey et al. 2010) as previously reported. Sex-specific differences in these and other pathways provide a molecular basis for the appearance of a sex-specific response to nutritional stressors and may also be used for non-invasive embryo sexing methods (Sturmey et al. 2010, Gomez et al. 2016).

Other pathways reported to exhibit sex differences include those related to apoptosis and embryo–maternal communication. The X-linked inhibitor of apoptosis XIAP is, as are most X-linked genes, upregulated in female embryos (Gutierrez-Adan et al. 2001), which is consistent with the notion that male embryos are more sensitive to oxidative-induced heat stress (Perez-Crespo et al. 2005). Nevertheless, under normal in vitro culture conditions, female bovine blastocysts seem to be more prone to apoptosis (Ghys et al. 2016). The differential apoptotic rates between sexes under different stressors may result in one sex being more susceptible than the other to blastomere loss, which may have consequences for subsequent development. Furthermore, sex differences may also affect embryo–maternal signaling, which is essential for proper late embryonic development and implantation. Interferon tau, IFNT, a major embryo-derived signaling molecule for pregnancy recognition in ruminants, and PGRMC1, a progesterone receptor, are upregulated in female bovine embryos (Larson et al. 2001, Arias-Alvarez et al. 2011, Bermejo-Alvarez et al. 2011b), and the embryokine CSF2 exerts a sex-specific response (Dobbs et al. 2014).

Finally, transcriptional differences between sexes may directly affect epigenetics in a sexually dimorphic manner, thereby exerting a direct impact on the appearance of sex-specific long-term developmental consequences. Apart from the X-linked genes already discussed, autosomal genes including both de novo DNA methyltransferases (DNMT3A and DNMT3B) and two genes related with histone methylation (HMT1 and ILF3) are upregulated in male bovine blastocysts compared to their female counterparts (Bermejo-Alvarez et al. 2008). These transcriptional differences are reflected in the methylation levels of specific sequences such as the repetitive sequence VNTR (Bermejo-Alvarez et al. 2008) and one differentially methylated region (DMR) in the imprinted gene IGF2 (Gebert et al. 2009), both being hypomethylated in female bovine blastocysts compared to males. Similar methylation differences are observed in closely related biological systems such as murine embryonic stem cells (ES), where XX cell lines are hypomethylated compared to XY lines (Zvetkova et al. 2005). Sexual dimorphism in histone modification may also arise, as differences in histone modifications methyltransferases of H3K4me3, H3K27me3 and H3K9me3, as well as DNA methyltransferases, have been observed in male and female E10 pig embryos (Gao et al. 2011).

Sexual dimorphism at the epigenetic level is directly bound to the appearance of sex-specific epigenetic-based phenotypes. An example of sex-biased epigenetic alteration is Beckwith–Wiedemann syndrome, a human epigenetic disorder to which the so-called ‘Large Offspring Syndrome’ in animals is considered equivalent (Farin et al. 2004). This syndrome is caused by altered methylation patterns at imprinting domains; it occurs at a relatively high frequency in monozygotic twins, and in almost all cases, the affected twins are female (Lubinsky & Hall 1991, Weksberg et al. 2002). External stressors acting during the periconceptional period have also been reported to exert a sex-specific effect. In sheep, a methyl-deficient maternal diet during the periconceptional period leads to epigenetic alterations, which are more pronounced in males than in females (Sinclair et al. 2007). In rats, a restriction of dietary protein supplementation during the periconceptional period results in sex-specific cardiovascular and behavioral diseases in the offspring (Kwong et al. 2000, Watkins et al. 2008b), with females being more susceptible (Fleming et al. 2015b). The effect of this low-protein diet was mediated through changes in branched-chain amino acids and insulin levels in the uterine fluid, which were detected by embryos via the mTOR signaling pathway. These embryos were able to activate compensatory mechanisms in order to enhance maternal nutrient retrieval, by stimulating trophectoderm and primitive endoderm proliferation, endocytosis and cellular motility (Eckert et al. 2012, Sun et al. 2014, 2015). Although these responses protected foetal growth, at the same time, they led to abnormal growth and increased adult adiposity, resulting in adverse long-term effects, with female offspring more severely affected. Moreover, these effects were observed even when the embryos were transferred to mothers on a normal nutritional regime (Watkins et al. 2008a, 2010, 2011). Consistent with these studies, other authors have reported a greater response to stress by the female placenta compared to the male placenta in terms of gene expression (Clifton 2010, Osei-Kumah et al. 2011).

Sex-specific long-term effects mediated by assisted reproductive technologies

Assisted reproductive technologies may constitute an environmental stressor to the preimplantation embryo. Several studies reporting long-term consequences of in vitro culture or other ART identified a sex bias in the frequency and nature of the long-term effect (Fernandez-Gonzalez et al. 2004, Sjoblom et al. 2005, Feuer & Rinaudo 2012, Tarin et al. 2014). These deleterious effects have pointed to epigenetic alterations produced by ARTs. A number of reports have demonstrated that in vitro culture conditions induce alterations and errors in the epigenetic reprogramming of bovine embryos, leading to alterations in their DNA methylation pattern (Fernandez-Gonzalez et al. 2004, Niemann et al. 2010, Salilew-Wondim et al. 2015). Studies in mice have demonstrated that genomic imprinting in preimplantation embryos can be disturbed by specific culture conditions (Doherty et al. 2000, Khosla et al. 2001). Furthermore, mouse embryos cultured to the blastocyst stage using commercially available sequential media have been shown to suffer a shift in the expression of some non-imprinted genes (Morgan et al. 2008). Recently, we have shown that the presence of oviductal fluid within the culture medium during in vitro culture of bovine embryos provoked alterations of the methylation level of regions CpG in the developmental genes MTERF2, ABCA7 and OLFM1 and in the retrotransposon LINE-1 at the blastocyst stage when compared to control conditions using conventional culture medium supplemented with BSA (Barrera et al. 2017). Others have also shown that the methylation levels of the embryonic epigenome are affected by culture conditions in a developmental stage-dependent manner (Salilew-Wondim et al. 2015). These epigenetic alterations, especially those provoked under suboptimal in vitro culture conditions, have been blamed as the cause of diverse disorders in the offspring, such as the ‘Large Offspring Syndrome’ in cattle and sheep (Chen et al. 2013). This condition is characterized by a disproportionate growth and reduced viability of the foetus. Similar effects are observed when mouse embryos are cultured in vitro with serum, but only in females, together with sex-dependent behavioral abnormalities (Fernandez-Gonzalez et al. 2004). However, in a similar model in mice, increased body weight and decreased brain size were only observed in males when they were cultured in the presence or absence of a specific growth factor, granulocyte-macrophage colony-stimulating factor, also known as colony-stimulating factor 2 (CSF2) (Sjoblom et al. 2005). CSF2 is a cytokine produced in the oviduct and endometrium that has been implicated in developmental programming (Giacomini et al. 1995, de Moraes et al. 1999, O’Leary et al. 2004, Nahar & Kadokawa 2016) and its expression is modified by environmental factors. For example, seminal plasma triggers CSF2 expression (Tremellen et al. 1998, O’Leary et al. 2004, Bromfield et al. 2014), while maternal obesity can suppress it (Nahar & Kadokawa 2016). In cattle, treatment with CSF2 from Day 5 to Day 7 after fertilization improved blastocyst development for female but not for male embryos. Furthermore, this treatment decreased embryo elongation and intrauterine accumulation of IFNT in females and affected the transcriptome and methylome in a different way for males and females (Siqueira & Hansen 2016).

Metabolic alterations in the offspring associated with ARTs are also dependent on sex according to different studies. In mice, long-term effects associated with in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI) and somatic cell nuclear transfer (SCNT) were found to be sex specific, with females showing altered glucose clearance, higher body weight and adiposity (Scott et al. 2010a). In agreement, another study reported sex-specific differences in sterol metabolism, redox state, mobilization and oxidation of fatty acids after IVF in murine offspring, with females being more predisposed to increased fat accumulation (Feuer et al. 2014). However, in another study in mice produced from IVF, altered postnatal growth and glucose intolerance were only observed in males (Donjacour et al. 2014). Additional sexual dimorphic patterns induced by IVF were reported by Tan and coworkers (Tan et al. 2016). In this study, female embryos were more susceptible to apoptosis during the preimplantation and mid-gestation stages. Later in gestation, both males and females showed reduced placental angiogenesis, but compensatory placental overgrowth was more evident in males. Finally, overgrowth was only observed in males after birth (Tan et al. 2016). Our group has also reported a large number of sex-dependent alterations after ICSI using fresh or frozen sperm, including behavioral alterations, higher body weight and organ size and increased tumor incidence in females (Fernandez-Gonzalez et al. 2008, Ramos-Ibeas et al. 2014).

Sex differences after implantation: another source for sex-specific long-term effects

Once the embryo has been implanted and XCI has been accomplished, transcriptional sex differences driven by sex chromosome dosage are reduced, but not abolished (Wijchers et al. 2010), compared to preimplantation development. However, once the gonads develop, a new factor for sexual dimorphism arises: sex hormones. From an evolutionary point of view, sex differences in foetal survival is seen as a way to adjust the energy invested by parents in male vs female offspring to the postnatal environment faced by the offspring (Trivers & Willard 1973, Koskela et al. 2009). According to the Trivers–Willard hypothesis, mothers with plentiful resources invest in the sex with a reproductive disadvantage while those mothers facing adverse environment preferentially produce offspring of the sex with a greater chance of reproductive success (Trivers & Willard 1973). The dominant concept is that female and male foetuses have different growth strategies, leading to differential survival and pregnancy outcomes. Thus, by their greater sensitivity to the maternal environment, females would follow modest growth changes and therefore better adaptation to deleterious signals such as maternal asthma and a restricted or high-fat diet. In contrast, male foetuses show a more divergent growth curve and as consequence poor adaptation to adverse environment (Clifton 2010, Eriksson et al. 2010, Cox et al. 2013). Although multiple observations support this hypothesis, there is a lack of solid experimental data from animal models in the literature unequivocally proving that male growth and survival in the womb is more affected than that of females when the environment is perturbed. It has been reported that a high-fat diet provokes under-methylation only of female placentas in mice, which is indicative of an active response to this stressor (Gallou-Kabani et al. 2010); this was confirmed by another study showing that female placenta was more responsive to nutritional perturbations by more significant changes in the placental transcriptome (Mao et al. 2010). In rats, this higher adaptation was also observed for the female placenta in contrast to its male counterpart in response to ethanol by decreasing the 11β-hydroxysteroid dehydrogenase-2 activity (Wilcoxon et al. 2003). In addition, in humans, the female placenta responds to antenatal steroid administration by upregulating 11β-hydroxysteroid dehydrogenase-2 (Stark et al. 2009). These observations suggest that male foetuses are less buffered than females against certain environmental insults. Thus, under various stressors, male foetuses exhibit higher late foetal mortality due to a greater in utero vulnerability (Eriksson et al. 2010), and their foetal growth is more affected than that of females (Sundrani et al. 2017) (Fig. 1).

Placental response to environmental stress

The placenta is a gestational interface between mother and foetus that controls foetal development and growth through the exchange of gases, nutrients and waste products and also in the production of pregnancy-induced hormones, growth factors and immune response. Thus, the adaptive properties of this organ are essential for foetal survival during specific stresses and seem to be the main reason for the sex differences associated with stress observed during early and later foetal stages, affecting adult life as well (Gabory et al. 2013). The reported higher protection of female offspring in utero (Wilcoxon et al. 2003, Vickers et al. 2011) could be due to inherent sex differences in the placenta making the female placenta more adaptive and plastic. The sex differences of the human placenta have been revealed at the transcriptomic level. Global transcriptomic analyses revealed that females possess more upregulated autosomal genes, including immune-regulating genes, than males (Sood et al. 2006). This may indicate that human female placentae respond better to potential infections. In contrast, analyses of isolated cells derived from human placentae revealed sex-dependent differences in four placental cell types: cytotrophoblasts, synctiotrophoblasts and arterial and venous endothelial cells. In these analyses, male placentae showed enrichment of signaling pathways reported to mediate graft vs host disease and other transcripts involved in immune function and inflammation (Cvitic et al. 2013). The authors suggested that male placentae may be forced to upregulate immune-associated transcripts in an attempt to counteract the response of the maternal immune system due to a reduced maternal–foetal compatibility compared to female placentae. It has also been suggested that the structural and functional differences may contribute to enhance male susceptibility to in utero environmental perturbations (Kalisch-Smith et al. 2016). The placenta of human males invades more deeply into the spiral arteries than female placenta. In contrast, the latter exhibits more effective placental surface differentiation (Alwasel et al. 2014). In the spiny mouse (Acomys cahirinus), the female placenta contains a larger labyrinth but smaller spongy region than that of the male, and genes related to glucose transport were found to be differentially expressed among sexes in the two placental regions (O’Connell et al. 2013a). Based on rodent literature, it has been suggested that perturbation during early placental development may have a greater impact on viability and growth of the female foetus while those occurring later in gestation may preferentially affect the male foetus (Kalisch-Smith et al. 2016).

Placental response to maternal diet

All these inherent differences between male and female placenta are likely behind the differential response to the maternal environment. The available literature demonstrates that environmental exposures can disrupt placental morphology, epigenetic regulation and gene expression in a sex-dependent manner (Tarrade et al. 2015). The placenta adapts to the maternal diet and metabolic status altering foetal nutrient supply. This is done in a different way in male and female placentae showing different profiles of energy metabolism including glycogen storage and metabolism throughout gestation (O’Connell et al. 2013b). Animal studies have observed transcriptional sex differences in placentae under different maternal dietary regimes. In mice, it has been found that a low-fat vs high-fat diet deregulates significantly more genes in female than in male placentae (Mao et al. 2010) mainly affecting cell signaling of immune cells and uptake and metabolism of amino acids. In contrast, the genes affected in male placenta were related to development and function of the vascular system as well as uptake and metabolism of glucose and fatty acids (Gabory et al. 2012). These differences in gene expression can be explained by changes in epigenetic regulation. Thus, female placentae were found to be hypomethylated in response to a high-fat diet in mice (Gallou-Kabani et al. 2010, Gabory et al. 2012). In rats, high-fat and high-salt diets lowered placental size of males, increasing the expression of genes associated with metabolism and pro-inflammatory mediators, which has been related to future cardio-metabolic disturbances (Reynolds et al. 2015). In rabbits, high-fat and high-cholesterol diets provoke higher accumulation of triacylglycerol in males while they upregulate genes of the lipid pathway in females (Tarrade et al. 2013). In non-human primates, nutritional restriction has been reported to suppress genes related to programmed cell death and enhance genes associated with cell proliferation in female placentae. In contrast, male placentae showed less responsiveness in terms of the number of affected genes and pertinent pathways (Cox et al. 2013). In humans, it has been reported that obese women show thicker and less efficient placentae showing significant alterations meant for adaptation only in the female placenta (Mandò et al. 2016).

Placental response to maternal psychological stress

In utero exposure to maternal psychological distress affects the function of the foetal hypothalamus–adrenal–pituitary (HPA) axis, which has implications for the development of diverse foetal tissues (Cottrell & Seckl 2009, Harris & Seckl 2011). Although this response to stress could be physiological, high stress and prolonged levels of prenatal stress and cortisol exposure can produce negative effects on foetal development (Laplante et al. 2004, Davis & Sandman 2010). In response to this signaling, differential sex-dependent responses have been reported in both human and animal studies at both normal and pathological distress levels (Sandman et al. 2013). In order to buffer the impact of maternal psychological stress, placentae express 11β-HSD2 that degrades cortisol to cortisone. Interestingly, the female placenta is more reactive than the male, and higher expression of 11β-HSD2 has been shown in female placenta exposed to glucocorticoid treatment than that of males (Stark et al. 2009). Treatments with glucocorticoids have been shown to induce other alterations such as increased placental oxidative stress, expression of pro-inflammatory cytokine and 5 alpha-reductase (Scott et al. 2009, Vu et al. 2009, Stark et al. 2011), showing a more pro-oxidative state in male placentae.

According to the hypothesis of DOHaD (Barker 2007), the glucocorticoids transmitted from mother to foetus during gestation could be exploited by the foetus to optimize development in preparation for survival and success after birth (Gluckman et al. 2009, Ellis & Del Giudice 2014). However, it has been argued that while sex-specific foetal growth strategies result in greater adaptive flexibility for females in the short term, especially under maternal distress, it increases the long-term risk of developmental psychopathology. Thus, anxiety and depression are two examples of stress-related psychopathology for which there are clear sex differences in presentation and prevalence (Altemus et al. 2014).

Response to sex hormones and endocrine disruptors

From the early stages of development, the foetus is very susceptible to steroid hormone exposure, which plays important roles in tissue and organ differentiation (Sundrani et al. 2017). Thus, androgens have a role not only in the maturation of the male foetus but also in the development of mammary gland and folliculogenesis in the female foetus. Changes in these hormones due to maternal distress or endocrine disruptors differentially affect male and female foetuses. Low levels of androgen affect the development of testes in male foetuses and ovaries and adrenal cortex in female foetuses (Abbott et al. 2006) and an excess provokes alteration in testicular development (Rojas-García et al. 2013) and induces masculine characteristics in female foetuses (Wolf et al. 2002), foetal growth retardation (Manikkam et al. 2004) and polycystic ovarian syndrome in adult life (Hogg et al. 2011). At the same level as the sex hormones, also affecting the overall development of the foetus, endocrine-disrupting chemicals (EDC) have been highlighted as the main effectors altering placental and foetal performance in a deleterious way. EDC has been shown to alter gene transcription, signaling pathways (Tan et al. 2013, Xu et al. 2015), DNA methylation patterns (Nahar et al. 2015), miRNAs (Avissar-Whiting et al. 2010) and placental structure (Tachibana et al. 2007). However, a sex-dependent placental response is still not strongly supported by the literature. Thus, the only evidence to date is the differential DNA methylation of AluYb8 in response to the xenoestrogen burden in human placentas as higher methylation in males and no response in females (Vilahur et al. 2014). Other studies have also suggested that EDC can affect imprinted genes in the placenta (Susiarjo et al. 2013, Shin et al. 2014), but sex differences were not explored. Further studies are thus essential in addressing this critical gap in our understanding of how environmental chemicals interact with sex to affect placental outcomes.

Conclusions

Exposure to environmental stressors during preimplantation and peri-implantation development occurring either in vivo, such as during maternal diet imbalance, or in vitro, due to ARTs, activates compensatory responses in the embryo. These responses are often sex specific, due to the marked sex differences in transcriptional profiles at these stages, and may lead to long-term consequences, given the relevant epigenetic changes occurring during these early stages of development. Later, during foetal development, sex-specific foetal and placental responses may determine sex-specific long-term consequences to the exposure of environmental stressors such as maternal diet, stress or the exposure to endocrine disruptors. The epigenetic marks induced by specific environmental factors need to be identified in order to improve our understanding of the ontology of chronic diseases in response to these environmental factors by taking into account that male and female embryos and fetuses respond differently to the same environmental insult. Advances in transcriptomic and epigenomic tools make it possible to uncover the epigenetic roots of chronic diseases and their link to environmental insults and sex.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work has been funded by the State Secretariat for Research, Development and Innovation of the Spanish Ministry of Economy, Industry and Competitiveness through the projects AGL2015-66145R, AGL2015-70140-R and AGL2014-58739-R. P Lonergan is supported by Science Foundation Ireland (13/IA/1983).

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    Pre- and peri-implantation embryo adaptations to environmental stress. Comparative pre- and peri-implantation embryo development in mammals. Critical events taking place during this developmental window (pluripotency emergence, epigenetic reprogramming, lineage allocation and X chromosome inactivation) render the embryo especially sensitive to environmental stress. Such embryos and the resulting foetus respond to stressors by sex-specific mortality or by adaptive responses in order to optimize their developmental program and offspring survival. The adaptability due to developmental plasticity (the ability of the genotype to produce different phenotypes in response to different environments) decrease throughout embryo and foetal development until early postnatal life. Later in adult life, this adaptability disappears and only the brain maintains a certain degree of plasticity. The female placenta (in pink), due to its higher adaptability, buffers more efficiently the impact of endogenous and exogenous stressors on the foetus and it is less compromised than male foetus (in blue) under similar stress conditions. However, compensatory mechanisms can compromise adult health according to the developmental origins of adult health and disease (DOHaD).

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